An iterative block-shifting approach to retention time alignment that preserves the shape and area of gas chromatography-mass spectrometry peaks

<p>Abstract</p> <p>Background</p> <p>Metabolomics, petroleum and biodiesel chemistry, biomarker discovery, and other fields which rely on high-resolution profiling of complex chemical mixtures generate datasets which contain millions of detector intensity readings, each uniquely addressed along dimensions of <it>time </it>(<it>e.g.</it>, <it>retention time </it>of chemicals on a chromatographic column), a <it>spectral value </it>(<it>e.g., mass-to-charge ratio </it>of ions derived from chemicals), and the <it>analytical run number</it>. They also must rely on data preprocessing techniques. In particular, inter-run variance in the retention time of chemical species poses a significant hurdle that must be cleared before feature extraction, data reduction, and knowledge discovery can ensue. <it>Alignment methods</it>, for calibrating retention reportedly (and in our experience) can misalign matching chemicals, falsely align distinct ones, be unduly sensitive to chosen values of input parameters, and result in distortions of peak shape and area.</p> <p>Results</p> <p>We present an iterative block-shifting approach for retention-time calibration that detects chromatographic features and qualifies them by retention time, spectrum, and the effect of their inclusion on the quality of alignment itself. Mass chromatograms are aligned pairwise to one selected as a reference. In tests using a 45-run GC-MS experiment, block-shifting reduced the absolute deviation of retention by greater than 30-fold. It compared favourably to COW and XCMS with respect to alignment, and was markedly superior in preservation of peak area.</p> <p>Conclusion</p> <p>Iterative block-shifting is an attractive method to align GC-MS mass chromatograms that is also generalizable to other two-dimensional techniques such as HPLC-MS.</p

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Concomitant radiochemotherapy plus surgery in locally advanced cervical cancer: update of clinical outcome and cyclooxygenase-2 as predictor of treatment susceptibility

OBJECTIVE: We have updated our findings on the efficacy of concomitant radiochemotherapy plus radical surgery in a larger series of patients (n = 54) with locally advanced cervical cancer (LACC). We also investigated the role of cyclooxygenase-2 (COX-2) in this clinical setting. METHODS: Radiotherapy was administered to the whole pelvic region (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2) and 5-fluorouracil (1,000 mg/m2) (both on days 1-4 and 27-30). Radical surgery was performed 5-6 weeks after the end of treatment. RESULTS: A clinical complete or partial response was observed in all 53 evaluable patients (75.5 and 24.5%, respectively). At pathological examination, 23 of 51 patients (45.1%) undergoing radical surgery showed complete response to treatment, 18 patients (35.3%) only had microscopic residual disease, 6 patients (11.7%) had a partial response and 4 (7.8%) had no change in their disease. When logistic regression was applied, the FIGO stage (chi2 = 5.28, p = 0.021) and tumor to stroma COX-2 ratio (chi2 = 4.72, p = 0.029) retained an independent role in the prediction of the pathologic response to treatment. The 3-year disease-free survival (DFS) was 75.2%, with local relapse-free survival of 86.2% and metastasis-free interval of 89.9% at 3 years. Cases with a high COX-2 ratio showed a shorter DFS than cases with a low COX-2 ratio (p = 0.016). A direct association was shown between COX-2 ratio values and risk of recurrence, as assessed by Cox analysis using COX-2 ratio values as a continuous covariate (chi2 = 3.94, p = 0.047). CONCLUSION: This study confirms the possibility of achieving a very high rate of pathological responses in LACC patients administered chemoradiation plus surgery (3-year DFS 75.2%). Moreover, COX-2 status may play a role in the prognostic characterization and prediction of tumor response

Douglas peritonectomy compared to recto-sigmoid resection in optimally cytoreduced advanced ovarian cancer patients: analysis of morbidity and oncological outcome

Rectosigmoidectomy (RR) with primary anastomosis or pelvic peritonectomy (PP) are often part of an optimal en bloc tumor resection in advanced ovarian cancer (AOC) patients with contiguous extension to or encasement of the reproductive organs, peritoneum of the cul-de-sac and sigmoid colon. We report our experience with two different surgical approaches in optimally cytoreduced AOC patients evaluating oncologic outcome and surgically associated morbiditie

Timing and Pattern of Recurrence in Ovarian Cancer Patients with High Tumor Dissemination Treated with Primary Debulking Surgery Versus Neoadjuvant Chemotherapy

PURPOSE: To compare the timing and pattern of recurrence in patients with advanced ovarian cancer (AOC) receiving primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). METHODS: We retrospectively evaluated a consecutive series of 175 stage IIIC-IV epithelial ovarian cancer patients, with diffuse peritoneal carcinomatosis documented at initial surgical exploration. Forty patients received complete PDS, and the remaining 135 were treated with NACT followed by IDS with absent residual tumor after surgery. RESULTS: No differences were observed in the distribution of clinical pathological characteristics at the time of diagnosis between the two groups. The median follow-up was 31 months (range 9-150 months). We observed 20 (50.0%) recurrences in the PDS group compared to 103 (76.3%) in the IDS group (p = 0.001). Duration of primary platinum-free interval (PFI) was shorter in IDS compared to PDS group (13 vs. 21 months, respectively; p = 0.014). A significantly higher percentage of patients in the IDS group experienced platinum-resistant recurrences (35.9 vs. 5.0%; p = 0.006) and carcinomatosis at the time of relapse (57.3 vs. 20.0%; p = 0.0021). Finally, in women with platinum-sensitive recurrence, we observed a shorter secondary PFI in the IDS compared to PDS group (p = 0.006). CONCLUSIONS: We documented a better behavior of recurrent disease in AOC patients with diffuse peritoneal carcinomatosis treated with complete PDS compared to women submitted to NACT followed by IDS with no residual tumor after surgery